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Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies.


ABSTRACT: Traditional drug safety assessment often fails to predict complications in humans, especially when the drug targets the immune system. Here, we show the unprecedented capability of two human Organs-on-Chips to evaluate the safety profile of T-cell bispecific antibodies (TCBs) targeting tumor antigens. Although promising for cancer immunotherapy, TCBs are associated with an on-target, off-tumor risk due to low levels of expression of tumor antigens in healthy tissues. We leveraged in vivo target expression and toxicity data of TCBs targeting folate receptor 1 (FOLR1) or carcinoembryonic antigen (CEA) to design and validate human immunocompetent Organs-on-Chips safety platforms. We discovered that the Lung-Chip and Intestine-Chip could reproduce and predict target-dependent TCB safety liabilities, based on sensitivity to key determinants thereof, such as target expression and antibody affinity. These novel tools broaden the research options available for mechanistic understandings of engineered therapeutic antibodies and assessing safety in tissues susceptible to adverse events.

SUBMITTER: Kerns SJ 

PROVIDER: S-EPMC8373379 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies.

Kerns S Jordan SJ   Belgur Chaitra C   Petropolis Debora D   Kanellias Marianne M   Barrile Riccardo R   Sam Johannes J   Weinzierl Tina T   Fauti Tanja T   Freimoser-Grundschober Anne A   Eckmann Jan J   Hage Carina C   Geiger Martina M   Ng Patrick Ray PR   Tien-Street William W   Manatakis Dimitris V DV   Micallef Virginie V   Gerard Regine R   Bscheider Michael M   Breous-Nystrom Ekaterina E   Schneider Anneliese A   Giusti Anna Maria AM   Bertinetti-Lapatki Cristina C   Grant Heather Shannon HS   Roth Adrian B AB   Hamilton Geraldine A GA   Singer Thomas T   Karalis Katia K   Moisan Annie A   Bruenker Peter P   Klein Christian C   Bacac Marina M   Gjorevski Nikolce N   Cabon Lauriane L  

eLife 20210811


Traditional drug safety assessment often fails to predict complications in humans, especially when the drug targets the immune system. Here, we show the unprecedented capability of two human Organs-on-Chips to evaluate the safety profile of T-cell bispecific antibodies (TCBs) targeting tumor antigens. Although promising for cancer immunotherapy, TCBs are associated with an on-target, off-tumor risk due to low levels of expression of tumor antigens in healthy tissues. We leveraged in vivo target  ...[more]

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